G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders

Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors. Identifying treatment targets is challenging because the diseases are resulting from heterogeneous biological, genetic, and environmental factors. Nevertheless, the increasing understanding of G protein-coupled receptor (GPCR) opens a new possibility in drug discovery. Harnessing our knowledge of molecular mechanisms and structural information of GPCRs will be advantageous for developing effective drugs. This review provides an overview of the role of GPCRs in various neurodegenerative and psychiatric diseases. Besides, we highlight the emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.


INTRODUCTION
The nervous system employs membrane receptors to detect extracellular stimuli and transmit signals across the cell membrane. As the largest membrane protein family, G protein-coupled receptors (GPCRs) allow the nervous system to respond accurately to external stimuli and internal states. GPCRs are structurally similar transmembrane proteins containing seven transmembrane (TM) α-helices linked by three extracellular loops and three intracellular loops. 1 The unique ligand binding pockets formed by the 7TM regions allow the receptor to engage with various stimuli, including neurotransmitters, nucleotides, amines, peptides, cytokines, and hormones in the extracellular environment (Fig. 1). 2 Through expressing GPCRs with different ligand-recognizing abilities, the nervous system could filter and select particular signals to respond. 3 Furthermore, the intrinsic ligand selectivity of neuronal GPCRs allows crosstalk and proper integration between signal transduction pathways. GPCRs drive signal transduction via two major modulators: heterotrimeric G protein and arrestins. Characterizing the physiological functions of GPCRs in the nervous system and pathological mechanisms in disease models could accelerate GPCR-targeted drug development.
The progressive dysfunction of neural tissues in the central and peripheral nervous systems is the hallmark feature of neurodegenerative diseases. Neurodegenerative diseases are increasing in the elderly population. 4 It is estimated that neurodegenerative diseases affect over 50 million people across the globe. 5 Alzheimer's disease, Huntington's disease, Parkinson's disease, and Multiple sclerosis are representative examples. Currently, there is no effective cure. The pathogenesis and underlying mechanisms of neurodegenerative diseases remain poorly understood. At present, symptom control is the primary treatment objective. 6 It is estimated that neurodegenerative diseases will become the second most common cause of death. 7 Alzheimer's disease and dementias are in the top-ten ranking leading cause of death globally. 8 Deposition of the insoluble and phosphorylated β-amyloid peptide (derived from amyloid precursor protein) in the brain parenchyma of Alzheimer's disease patients affects functions/regeneration of various forms of neurons. 9 The resulting widespread neuron damage affects synaptic communication leading to cognitive deficits, regional brain shrinkage, and brain atrophy; 10 Huntington's disease could appear in childhood or adolescence. Aberrant expansion of DNA segment containing CAG trinucleotide repeats in the huntingtin gene is a hallmark feature. 11 Large CAG repeat is associated with early symptoms manifestation. 12 Symptoms include poor coordination, chorea (involuntary dance-like movements), slow movement, seizures, and slurred speech; Parkinson's disease affects motion control. Rigidity, tremor, and slow movement (bradykinesia) are frequently observed. Risk factors include genetic polymorphism, chronic inflammation, and metabolic disorders. 13 Multiple sclerosis is a relapsing-remitting disease caused by an autoimmune attack in the central nervous system. Damage of myelin sheath in multiple areas by immune cells causes cognitive impairment, fatigue, muscle weakness, tremor, and vision problems. 14 Brain disorders are frequently associated with mental/psychiatric illnesses. 15 Mental illness is burdening the healthcare system with enormous unmet medical needs. 16,17 Serious mental illness is closely linked to reduced life expectancy due to a higher risk of cardiovascular morbidity and mortality. 18 Common mental illnesses include anxiety, depression, bipolar disorder, attention deficit hyperactivity disorder, and schizophrenia. Both children b Solvent-accessible surface. Hydrophobic surface (red); hydrophilic surface (white). c Activated GPCR opens cytosolic pocket for G protein coupling. d Heterotrimeric G protein, Monomeric Gαi, Gβγ. d Activated 5-HT2A receptor forms a cytoplasmic pocket which allows G-protein coupling  Human GPCR can be classified into five distinct subtypes: rhodopsin (class A), secretin (class B1), adhesion (class B2), glutamate (class C), and frizzled (class F). 1 To date, over 750 ligand-bound or apo-GPCR structures (including 96 CNS-related GPCRs) have been reported (Table 1). For details: https:// gpcrdb.org. The transmembrane helical core exhibits high similarity. The helical core forms the orthosteric binding pocket for cognate ligands. GPCR can be divided into three different functional regions: (1) extracellular region including N-terminus, extracellular loops (ECLs), and extracellular ends of the transmembrane helices are involved in ligand recognition and selectivity; 25 (2) intracellular region consisting of C-terminus, intracellular loops (ICLs) and intracellular ends of the transmembrane helices provide docking cavity for G proteins/ arrestins and interacts with different regulatory proteins such as GPCR kinases; 26 (3) helical core inbetween extracellular and intracellular region deliver and covert ligand signals via unique conformational change (Fig. 1b). 27,28 Activated receptors generate second messengers via the G protein. In heterotrimeric form, the G protein is inactive. After binding to the intracellular cavity formed by GPCR, the GDPbinding pocket on the Gα subunit of heterotrimeric G proteins is opened, facilitating subsequent exchange for GTP. 29 GTP is physiologically more abundant as compared to GDP. 30 The nucleotide exchange is a rate-limiting step in the G protein ADRB3 beta-3 adrenergic receptor, AGTR1 type 1 angiotensin II receptor, AGTR2 type 2 angiotensin II receptor, HTR1A 5-hydroxytryptamine receptor 1A, HTR1B 5-hydroxytryptamine receptor 1B, HTR1D 5-hydroxytryptamine receptor 1D, HTR1E 5-hydroxytryptamine receptor 1E, HTR1F 5-hydroxytryptamine receptor 1F, HTR2A 5-hydroxytryptamine receptor 2A, HTR2B 5-hydroxytryptamine receptor 2B, HTR2C 5-hydroxytryptamine receptor 2C, ACM1 muscarinic acetylcholine receptor M1, ACM2 muscarinic acetylcholine receptor M2, ACM3 muscarinic acetylcholine receptor M3, ACM4 muscarinic acetylcholine receptor M4, ACM5 muscarinic acetylcholine receptor M5, APJ apelin receptor, BKRB1 B1 bradykinin receptor, BKRB2 B2 bradykinin receptor, C5AR1 C5a anaphylatoxin chemotactic receptor 1, CCKAR cholecystokinin receptor type A, CCR1 cinnamoyl-CoA reductase 1, CCR2 C-C chemokine receptor type 2, CCR5 C-C chemokine receptor type 5, CCR6 C-C chemokine receptor type 6, CCR7 C-C chemokine receptor type 7, CCR9 C-C chemokine receptor type 9, CNR1 cannabinoid receptor 1, CNR2 cannabinoid receptor 2, CXCR2 C-X-C chemokine receptor type 2, CXC-R4 C-X-C chemokine receptor type 4, DRD1 D(1A) dopamine receptor, DRD2 D(2) dopamine receptor, DRD3 D(3) dopamine receptor, DRD4 D(4) dopamine receptor, EDNRB endothelin receptor type B, FFAR1 free fatty acid receptor 1, FPR1 fMet-Leu-Phe receptor, FPR2 N-formyl peptide receptor 2, GALR1 galanin receptor type 1, GALR2 galanin receptor type 2, CCKBR gastrin/cholecystokinin type B receptor, GHSR growth hormone secretagogue receptor type 1, GNRHR gonadotropin-releasing hormone receptor, GPBAR1 G-protein coupled bile acid receptor 1, HRH1 histamine H1 receptor, LPAR1 lysophosphatidic acid receptor 1, LSHR lutropin-choriogonadotropic hormone receptor, LT4R1 leukotriene B4 receptor 1, MC4R melanocortin receptor 4, MSHR melanocyte-stimulating hormone receptor, MTNR1A melatonin receptor type 1A, MTNR1B melatonin receptor type 1B, NK1R substance-P receptor, NPY1R neuropeptide Y receptor type 1, NPY2R neuropeptide Y receptor type 2, NTSR1 neurotensin receptor type 1, OPRD delta-type opioid receptor, OPRK kappa-type opioid receptor, OPRM mu-type opioid receptor, OPRL1 nociceptin receptor, HCRTR1 orexin/hypocretin receptor type 1, HCRTR2 orexin receptor type 2, OXYR oxytocin receptor, P2RY1 P2Y purinoceptor 1, P2Y12 P2Y purinoceptor 12, PAR1 proteinase-activated receptor 1, PAR2 proteinase-activated receptor 2, PTGDR2 prostaglandin D2 receptor 2, PTGER2 prostaglandin E2 receptor EP2 subtype, PTGER3 prostaglandin E2 receptor EP3 subtype, PTGER4 prostaglandin E2 receptor EP4 subtype, PTAFR platelet-activating factor receptor, lpar6a lysophosphatidic acid receptor 6a, BLT1 leukotriene B4 receptor 1, S1PR1 sphingosine 1-phosphate receptor 1, S1PR2 sphingosine 1-phosphate receptor 2, S1PR3 sphingosine 1-phosphate receptor 3, S1PR5 sphingosine 1-phosphate receptor 5, SSR2 somatostatin receptor type 2, SUCR1 succinate receptor 1, TBXA2R thromboxane A2 receptor, V2R vasopressin V2 receptor, GPR52 G-protein coupled receptor 52, GPR88 probable G-protein coupled receptor 88, GPR139 probable G-protein coupled receptor 139, GPR183 G-protein coupled receptor 183, MRGX2 Mas-related G-protein coupled receptor member X2, MRGX4 Mas-related G-protein coupled receptor member X4, CALCR calcitonin receptor, CALRL calcitonin gene-related peptide type 1 receptor, CRFR1 corticotropin-releasing factor receptor 1, CRFR2 corticotropin-releasing factor receptor 2, GHRHR growth hormone-releasing hormone receptor, GIPR gastric inhibitory polypeptide receptor, GLP1R glucagon-like peptide-1 receptor, GLP2R glucagon-like peptide 2 receptor, GCGR glucagon receptor, SCTR secretin receptor, ADGRG1 adhesion G-protein coupled receptor G1, ADGRL3 adhesion G protein-coupled receptor L3, GABR1 gamma-aminobutyric acid type B receptor subunit 1, GABBR2 gamma-aminobutyric acid type B receptor subunit 2, GRM1 Gα proteins: Gαs and Gαi/o Gαs (stimulatory regulator of adenylyl cyclase G protein activates adenylyl cyclase) promotes the generation of 3'-5'-cyclic adenosine monophosphate (cAMP) from ATP by adenylate cyclase. cAMP is essential for protein kinase A (PKA)-mediated signal transduction; 32 In contrast, Gαi/o suppresses adenylyl cyclase activity, which prevents cAMP accumulation and reduces PKA activity. cAMP is a crucial regulator of the phosphoinositide 3kinase/AKT murine thymoma viral oncogene homolog (PI3K/AKT) signaling pathway. It has been shown that PI3K/AKT is associated with the inflammatory response in multiple neurodegenerative diseases. [33][34][35] cAMP is also linked to calcium dynamics in neuronal cells and neurodegenerative diseases. Details can be found in the comprehensive review by Sobolczyk and Boczek. 36 Gα protein: Gαq/11 Gαq activates phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-biphosphate into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates protein kinase C, which phosphorylates various downstream signaling proteins. IP3 stimulates calcium efflux from the endoplasmic reticulum through specific IP3 receptors. Calcium signaling is essential for the release of neurotransmitters. 37,38 For instance, dysregulation of the dopamine D1 receptor-mediated PLC/IP3/Ca 2+ pathway in the anterior cortex of the brain is associated with mental illness in rats. 39 42 In psychiatric disorders, Ca 2+ signaling regulates neuronal connectivity, synaptic plasticity, and glial functions. 43 Gα protein: Gα12/13 Gα12/13 binding can stimulate Rho family GTPases. 44 Rho GTPases activate the cytosolic Rho protein by promoting GDP/GTP exchange. 45 Activated Rho is released from inhibitory protein, migrates to the plasma membrane, and modulates multiple downstream effectors. 46 One of which is ROCK1/2 (Rho kinase). The Rho-ROCK pathway is essential in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. 47 ROCK activity is closely associated with neuronal cell loss, impaired synaptic functions, and cytoskeleton modulation in central nervous system disorders. 47 Rho/ROCK signaling modulates the activity of transcription regulators such as AP-1, MRTF-A, YAP, NF-κB, and serum response factor. 47,48 Rho family GTPases are essential for axon guidance, cell polarity, and synapse formation. 49 It has been shown that Rho GTPase regulates neuronal cell survival by inhibiting AKT signaling. 50 GPCR kinases (GRKs) Activated GPCR is subjected to desensitization to protect the cell from sustained stimulation. 51 After peak response, ligand-bound receptor activity will return to basal level. 52 Receptor phosphorylation by a family of GPCR kinases (GRKs), including GRK1/7, GRK2/3, and GRK4/5/6, is an essential first step to switch off sustained signaling. 53,54 GRKs are second messenger-independent kinases (e.g., in contrast to PKA, which is dependent on cAMP levels). Serine/threonine residues on the GPCR carboxyl-terminal tail are common phosphorylation sites targeted by GRKs. 55 GRKs translocate from cytoplasm to plasma membrane and initiate receptor phosphorylation by binding to Gβγ. 56,57 GRK could also interfere with G protein binding through direct interaction. 58 GRK   Fig. 3 GPCR-G protein/arrestin complexes. a Crystal structure of arrestin 1 (PDB 1CF1) showing the membrane-anchoring c-loop. b Solventaccessible surface. Hydrophobic surface (red); Hydrophilic surface (white). c Biased signaling of serotonin 5-HT2B receptors. Activated 5-HT2B receptor (PDB 7SRQ) is preferentially coupled to Gαs protein (PDB 7SRR). The receptor could also couple to β-arrestin 1 (PDB 7SRS). Gαs and β-arrestin 1 engaged on the same cavity formed by the cytoplasmic receptor interface level is affected by inflammatory responses in neonatal and adult neurons. 59 GRK dysfunction is associated with cognitive impairment and tau hyperphosphorylation in Alzheimer-like pathology. 60 Colocalization of GRK with amyloid plaques is observed in brain tissues of Alzheimer's disease patients. 61 Patients of Parkinson's disease with dementia have increased GRK3/5 transcripts. 62 GRK might promote the formation of pathological Lewy bodies in sporadic Parkinson's disease, but the mechanism is yet to be defined. 63 In psychiatric disorders, upregulating brain GRKs are observed in schizophrenia and major depression. 64,65 Arrestins in GPCR desensitization Active GPCR is ready for the arrestins (signal terminators) binding after GRK phosphorylation. Arrestins can be classified into visual arrestins (arrestin 1 and arrestin 4) and non-visual arrestins (β-arrestin 1/2 or arrestin 2/3). Visual arrestins express exclusively in retina photoreceptors. They regulate light-activated rhodopsin signaling. 66,67 β-arrestin 1/2 are ubiquitously expressed cytoplasmic proteins (Fig. 3a, b). 52 β-arrestins and G proteins compete for the receptors. They bind to the same inter-helical cavity on the intracellular region (Fig. 3c). 68 β-arrestin reduce G protein singling by hindering interaction between receptor and heterotrimeric G proteins. Further, β-arrestins facilitate receptor recycling by promoting internalization and cellular trafficking. 69,70 The C-edge of arrestin protein with proximity to the membrane surface functions membrane anchor to stabilize the arrestin-active receptor complex (Fig. 3a). 71 Recent studies illustrate the association of β-arrestin in multiple physiological functions and neuropsychiatric disorders. 72,73 Phosphorylation of PI3K/AKT is remarkably reduced in the β-arrestin 2-deficient adult neural stem cells, indicating the crucial role of β-arrestin 2-PI3K/Akt pathway in adult hippocampal neurogenesis. 74,75 Biased signaling of GPCRs G protein-biased signaling is regarded as the canonical signaling pathway employed by GPCRs. β-arrestin can modulate GPCR signal transduction in G proteinindependent mechanism. β-arrestin can use the receptor as a structural component to generate an intracellular signaling complex consisting of agonist-occupied receptor and nonreceptor tyrosine kinases (c-Src). 76 β-arrestin can maintain ERK signaling by acting as a scaffold for ERK mitogen-activated protein kinase. 77 Other downstream effectors of β-arrestins include phosphatases and transcription factors. 78 β-arrestins can act as a scaffold protein for specific downstream effectors. 79,80 In the mouse model, β-arrestin 2 exerts anti-inflammatory functions by inhibiting nuclear factor kappa-B. 81 Maintaining the arrestin-dependent signaling of M1 muscarinic acetylcholine receptor can prevent the insoluble misfolded proteins  82 β-arrestin is important for astrocyte-mediated pro-inflammatory cytokine production. 83 In mouse Parkinson's disease models, β-arrestin 2-biased ligands suppress glia-derived inflammation and prevent neuron loss. 84 IL-1β produced by the inflammation site is suppressed by β-arrestin 2. 84 As compared to agonists which facilitate G protein and β-arrestin signaling at the same time, a β-arrestin-biased agonist for δ-opioid receptor can effectively control anxiety-like behaviour by activating ERK1/2 in the limbic structures of the brain. 85 Hence, identifying therapeutic modulators that could preferentially stabilize GPCR structure for G proteins or β-arrestins is important for developing effective treatments for neurodegenerative and psychiatric diseases.
Examples of GPCR-regulated modulators in disease development β-site APP cleaving protein 1 (BACE1). The proteolytic activity of BACE1 promotes the generation of β-amyloid (Aβ) peptides from amyloid precursor protein in Alzheimer's disease. 86 BACE1 expression can be activated by muscarinic acetylcholine receptor M1/M3 via PKC and MAP kinase signaling cascades. 87 BACE1 activity is modulated by other GPCRs, such as the A2A and deltaopioid receptors. 33 It has been shown that selective activation of the M2 receptor will suppress BACE1 expression via PKA-mediated signaling events. 33 cAMP-response element binding protein (CREB). GWAS analysis indicates that genes involved in the cAMP/PKA/CREB pathway are genetically associated with schizophrenia and bipolar disorder. 88 CREB is a transcription factor activated by phosphorylation after GPCR activation. The binding of CREB to a specific cAMP response element (CRE) in the transcription regulatory region enhances particular gene transcription. For instance, neurotransmitteractivated dopamine D1 receptor on dopaminergic neurons can elicit transcription brain derived growth factor (BDNF) and other neurotrophins. 89 In patients with bipolar disorder and schizophrenia, CREB expression is remarkably reduced in the dorsolateral prefrontal cortex and cingulate gyrus. 90 While CREB protects neuronal cells in neurogenerative diseases, constitutively active CREB can reduce hippocampal neuron numbers and trigger sporadic epileptic seizures. 91,92 It has been shown that the CREB modulator could enhance synaptic plasticity, which is beneficial for schizophrenia treatment. 89 DARPP-32 and PP1. DARPP-32 (dopamine-and cyclic-AMPregulated phosphoprotein of molecular weight 32,000) regulates neuronal excitability levels by prolonged depolarizations and voltage oscillations. 93 DARPP-32 is the downstream target of Gicoupling receptors such as the D2 dopamine receptor. DARPP-32 functions as a protein phosphatase-1 (PP1) inhibitor, a eukaryotic serine/threonine protein, upon phosphorylation at Thr-34 by PKA. PP1 is a phosphatase with multiple physiological functions. PP1 controls clock component PER2 accumulation in neurons, influencing circadian rhythm by light-mediated clock resetting. 94 PP1 is an inducer of long-term synaptic depression in the hippocampus. 95 Dysregulation of glutamate and dopamine signaling is common in neurodegenerative and neuropsychiatric disorders. Quantitative modeling results suggested that DARPP-32 could integrate dopamine and glutamate signals in striatal neurons. 96 PP1 signaling reduces GABA(A) receptors in neostriatal medium spiny neurons depending on PKA and DARPP. 97

GPCRS IN NEUROPSYCHIATRIC DISEASES
Class A GPCR (rhodopsin) Structural insights. Class A GPCR is the most heavily investigated GPCR family for drug development. Ligand binding to the unique pocket stabilizes GPCR in a particular conformation. 98 Comparative analysis reveals that the outward bending/rotation of intracellular TM6 is a universal structure feature of receptor activation throughout the GPCR superfamily (Fig. 4a). 98 Hydrophobic packing interactions between the transmembrane helices help to maintain the active conformation of TM6. 99 Apart from TM6, rearrangements of other transmembrane helices, including TM3/5/7, open the intracellular milieu to facilitate recruitment of G protein. 100 Class A GPCR has a consensus binding interface for G protein coupling. 101 The receptors employ unique structure motifs as microswitches to transmit external stimuli (Fig. 4b). D 3.49 R 3.50 Y 3.51 motif (Ballesteros-Weinstein number) at the intracellular region of TM3 forms the classic "ionic lock" with E 6.30 on TM6 to constrain the receptor in the ground state. 102,103 Disruption of the ionic lock is an activation feature of class A GPCRs. 104 Side chains of Y 7.53 (NPxxY motif) on TM7 and W 6.48 (CWxP motif) on TM6 are subjected to orientation rearrangement during receptor activation. 105,106 The P 5.50 I 3.40 F 6.44 motif, formed by a group of hydrophobic residues on TM3/5/6, is also a crucial switch for receptor activation. 107 Polar interactions and aromatic stacking interactions between the conserved aromatic residues are frequently observed in the ligand binding region of activated class A GPCRs. 27 Acetylcholine receptors (muscarinic). Acetylcholine is a neurotransmitter employed by cholinergic neurons in the brain and spinal cord. 108 Muscarinic acetylcholine receptors in the central and peripheral nervous systems have five distinct subtypes. M1, M3, and M5 receptors are excitatory M1-like receptors. 109 In contrast, M2-like receptors (M2 and M4 receptors) inhibit adenylyl cyclase activity. All the subtypes are detected in the brain. M2 and M3 receptors are also found in peripheral tissues. 110 Reduced acetylcholine signaling due to the loss of cholinergic neurons is common in Alzheimer's disease. 111 Amyloid-β proteins could interrupt the interaction between the M1 receptor and G protein. 112 M1 receptor-knockout mice show Alzheimer's diseaselike pathology with age-dependent cognitive decline. 113 M1 receptor function is impaired by the binding of tau protein, a microtubule-associated protein in the extracellular matrix, which is toxic in secreted form; 114,115 Autoantibodies to recombinant human M1 receptors are detected in patients with schizophrenic disorders, mood disorders, and other psychiatric disorders. 116,117 The M1 receptor is a promising target for schizophrenia treatment. Allosteric modulation of M1 receptor activity could improve cognitive performance with antipsychotic activity. 118 However, substantial loss of cortical M1 receptor might affect the efficacy of positive allosteric modulator. 119 M2 receptor reduction is noted in the frontal cortex of Alzheimer's disease patients. 120 Suppressing M2 receptor expression with siRNA alters the expression of β-site APP cleaving protein. This transmembrane aspartic endopeptidase is involved in beta-amyloid formation. 121 M2 receptor is suspected to be related to the major depressive disorder and bipolar disorder development. 122 M2-encoding gene is genetically associated with the cholinergic dysfunction seen in mood disorders. 122 M3 receptor level is remarkably reduced in the post-mortem frontal cortex tissues of patients with bipolar disorder. 123 However, conflicting results are observed in another study cohort. 124 Genetic variants of the M3 receptor-encoding gene are associated with abnormal neural connectivity in schizophrenia and cannabisinduced hallucinations. 125,126 Acetylcholine elevation is observed in Parkinson's disease. [127][128][129] Targeting the M4 receptor with various antagonists showed promising treatment results for Parkinson's disease. 130,131 M4 receptor is abundantly expressed in striatal neurons, which regulates the balance between acetylcholine and dopamine responses. 132 M4 receptor promotes the development of the dopamine hypersensitivity phenotype of schizophrenia. 133 It has been shown that the M5 receptor can potentiate drug addiction by reinforcing rewarded behavior. 134 Adenosine receptor. Adenosine (A1A, A2A, A2B, A3A) receptors are synaptic modulators that transmit inhibitory signals from adenosine to excitatory synapses. 135 Adenosine is also known as a "retaliatory metabolite" as it is produced exponentially from tissue under stress. 136 Astrocytes release adenosine to modulate synaptic transmission during hypoxia. 137 A1A and A2A receptors exhibit widespread expression in the brain. 138 A1A and A3A receptors are Gi-coupling receptors. In contrast, A2A and A2B receptors prefer Gs for downstream signaling.
Although dopamine-replacement therapy is the mainstay treatment for Parkinson's disease, it remains challenging to manage dyskinesia during replacement treatments. 139 Animal study reveals that activating the A2A receptor will reduce the agonistic effects of dopaminergic D2 receptor-targeting drugs. 140 As the A2A receptor is colocalized with D2 dopaminergic receptors, it is suggested that interactions between A2A and D2 receptors might be involved in the pathophysiology of Parkinson's disease. 141 Epidemiological data support that caffeine (a naturally occurring methylxanthine) consumption might reduce the risk of depression or depressive symptoms. 142,143 The psychoactive function of caffeine is mediated via the non-selective antagonistic action on A1/A2A receptors. 144 How A1/A2A receptors regulate depression-like behaviour remains unclear. 145 It should be noted that caffeine at high doses might function other than adenosine receptor antagonists causing insomnia and anxiety. 146,147 Activated A2A receptor suppresses nitric oxide (NO) production by inhibiting NO synthetase. 12 NO signaling is associated with various neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. 148 NO is a mediator of neuroinflammation, which triggers the microglial to release proinflammatory factors. 149 NO induces protein S-nitrosylation (covalent addition of a NO group to a cysteine thiol/sulfhydryl), imposing endoplasmic reticulum stress in neurons. 150,151 As A2A receptor activation affects synaptic plasticity and introduces memory deficits, antagonizing the A2A receptor might be helpful to control age-related cognitive impairments in Alzheimer's disease. 152 Adrenergic receptor. Brain adrenergic receptors on neurons and glia are activated by the monoamine neurotransmitter norepinephrine (produced primarily in the locus coeruleus of the brain stem) and epinephrine. 153 Norepinephrine is produced from dopamine and converted into epinephrine. Norepinephrine and epinephrine released at synaptic junctions in the autonomic nervous system control classical fight-or-flight response. 154 Norepinephrine controls response to environmental changes by regulating neuronal excitability. 155 Epinephrine and norepinephrine also affect intelligence. 156 Human has 2 adrenergic receptor subtypes: α-adrenergic (α1, α2A, α2B, α2C) receptors and β-adrenergic (β1, β2, β3) receptors. All the subtypes can be detected in the brain tissues.
Adrenergic receptor protects the central nervous system from uncontrolled inflammatory responses. 157 In the neonatal Lewis rats model, norepinephrine protects neuronal damage from inflammation. [158][159][160][161] Blocking β-adrenergic receptors signaling with beta-blockers (β-adrenergic antagonists) could exacerbate neuroinflammation in a mouse model of Alzheimer's disease. 162 Patients of Alzheimer's disease and Parkinson's disease show profound cell loss in locus coeruleus. 163 Amyloid Aβ affects norepinephrine production and alters adrenergic receptor signaling in Alzheimer's disease; 164 Low norepinephrine level is linked to mood disorders such as anxiety, depression, and attention deficit hyperactivity disorder. 156 α2-adrenergic receptors are established targets for antidepressant therapy. 165 Depressed suicide victims showed high α2A-adrenergic receptor in the prefrontal cortex. 166 Presynaptic α2-adrenergic receptor is an auto-receptor with the highest affinity to norepinephrine. Activated α2-adrenergic receptor inhibits norepinephrine synthesis and release. 167 Thus, antagonizing presynaptic α2-adrenergic receptors could benefit depression treatment by enhancing norepinephrine release. 168 Cannabinoid receptor. Cannabinoid signaling is involved in nociception, neurotransmission, and neuroprotection. 169 It is also engaged in learning, memory, motor, food intake, anxiety, pain perception, and fear memories. 170 Cannabinoid receptor type 1 (CB-1) is the primary subtype in the central nervous system. In comparison, the CB-2 receptor is mainly found in immune tissues. 171 Cannabinoid receptors in the presynaptic nerve terminals can be activated by endogenous lipid endocannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA; anandamide). 172 2-AG is a full agonist for cannabinoid receptors, while AEA is a weak partial agonist. 173 Cannabinoid receptors can also be activated by phytocannabinoids such as Δ9-tetrahydrocannabinol and non-euphoric cannabidiol (CBD) extracted from cannabis. 174,175 The CB-1 receptor is the dominant subtype in the brain. 176,177 CB-1 receptor can be found in different neuronal types (e.g., GABAergic, glutamatergic, and serotonergic neurons) and controls cholinergic transmission. 178,179 Exogenous administration of endocannabinoids protects neurons from β-amyloid (Aβ) neurodegeneration and apoptosis. 180 Targeting cannabinoid receptors can improve spasticity (increase in muscle stiffness) and central neuropathic pain in patients with multiple sclerosis. 181 Substantial reduction of CB-1 receptor in lateral globus pallidus and substantia nigra pars reticulata is associated with neurodegeneration in Huntington's disease. 182,183 Genetic polymorphisms on the CB-1 receptor are a risk factor for schizophrenia. CBD treatment is effective for neuroinflammatory-derived conditions such as epilepsy and anxiety. 184 The pathological functions of the CB-2 receptor in inflammatory conditions (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, stress response, and depression) are under active investigation. 185,186 Inflammation is a driving factor of depression and could counter the effects of antidepressant therapies. 187 CB-2 receptor-overexpressing mice showed a significant reduction in depressive-related behaviors. 188 In contrast, pro-inflammatory chemokines and cytokines are markedly reduced in the brain of CB-2 receptor-deficient mice. 189 CB-2 receptor can suppress microglial activation and prevent pro-inflammatory mediators release. 190,191 In bipolar disorder, a neuropsychiatric disorder presenting with mood fluctuation, selective activation of the CB-2 receptor can stabilize mood and reduce mood swings. 192 Other receptors for endogenous cannabinoids: GPR12, GPR18, and GPR55. GPR12 is phylogenetically related to the cannabinoid (CB-1 and CB-2) receptors. 193 GPR12 is a constitutively active receptor. 194 Apart from cannabidiol, lysophospholipid sphingosine 1-phosphate and phingosyl-phosphorylcholine are potential endogenous ligands for GPR12. 193,195 GPR12 expressed mainly in the central nervous system (frontal cortex, piriform cortex, thalamus, hypothalamus, hippocampus, amygdala, and olfactory bulb). 196 In mice, GPR12 expresses in the area controlling emotion and metabolism. 195 GPR12 promotes neurite outgrowth by activating ERK1/2 signaling. 197 Other functions include pain control, neurite outgrowth, and regeneration. 193 SNP microarraybased genome-wide association study reveals a close association between GPR12 and antipsychotic response in schizophrenia treatment. 198 GPR18 and GPR55 also act as receptors for endogenous cannabinoids 2-AG and AEA. 199,200 GPR18 and GPR55 exhibit high structural similarity. 201 GPR18 regulates polymorphonuclear cell infiltration and protects organs from acute immune responses. 202 It has been shown that GPR18 could interact with the CB-2 receptor in activated microglia of Alzheimer's disease model; 203 GPR55 expresses predominantly in the brain. 204 The receptor can be activated by endocannabinoids, phytocannabinoids, synthetic cannabinoid ligands, and lysophosphatidylinositol. 205 GPR55 antagonist exhibits anti-inflammatory functions by modulating GPR55-expressing immune cells such as monocytes and microglia. 206 Given the high expression of GPR55 in the striatum, GPR55 signaling is suspected to be involved in motor impairment in Parkinson's disease. 207 Dopamine receptor. Dopamine is a catecholamine neurotransmitter in the brain. Dopamine/ dopamine receptors are crucial for motor function, cognition, learning, and memory. 208 There are two receptor subtypes: D1-like (D1 and D5) and D2-like (D2, D3, and D4). 209 D1 and D2 receptors are the most abundantly expressed dopamine receptor subtypes in the brain. 210 D1 and D2 receptors are significantly reduced in asymptomatic Huntington's disease patients. 12 In the early stage of Huntington's disease, dopamine signaling is associated with the development of dance-like movements (chorea). Clinical studies show that dopamine receptor blockers or depleting agents control motor dysregulation, especially chorea. 211 In the late stage, however, a remarkable reduction in dopamine/ dopamine metabolite level is observed. 212 The D1 receptor is remarkably reduced in patients presenting mild to moderate functional impairment. 213 It is noted that targeting the dopaminergic signaling cascade might lead to rapid cognitive decline in Huntington's disease patients. 214 Disturbances in the dopaminergic system are frequently observed in other neurodegeneration disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. 215 Reduced dopamine receptors are correlated with the progression of Alzheimer's disease; 216 Loss of dopaminergic neurons is a hallmark feature of Parkinson's disease. Activating D2-like receptors (D2/3 receptors) or increasing circulating dopamine are effective treatment strategies for symptomatic Parkinson's disease; 217 Dopamine dysregulation contributes to the demyelinating process (resulting from autoimmune attack) in multiple sclerosis. 218 Dopamine can modulate pro-inflammatory cytokines secretion in T helper Th17 cells in uncontrolled neuroinflammatory responses. 219,220 The development of β-arrestin-biased modulators might improve treatment outcomes and avoid side effects. Dopamine receptor agonist exhibits mild to serious side effects. 221 This is partly caused by the activation of both G proteins and the β-arrestin signaling cascade. 222,223 Many antipsychotics could interfere with dopamine-dependent β-arrestin 2 recruitment. 83 Selective activating the D2 receptor-β-arrestin pathway with biased agonist is beneficial to correct dopamine signaling in schizophrenia. 224 Histamine receptor. Histamine is an inflammatory biogenic amine synthesized from L-histidine. Histamine stimulates peripheral immune cells to release pro-inflammatory cytokines. In the central nervous system, histamine signaling in the tuberomammillary nucleus (TMN) controls sleep-wake, circadian and feeding rhythms. 225 Elevated histamine increases blood-brain barrier permeability, allowing peripheral immune cells to enter and act on brain parenchyma. 226 Four different histamine (H1-H4) receptors are reported. 227 H1 and H2 receptors are expressed in the brain, central nervous system, and peripheral tissues. 225 H1 receptor activation promotes neuron differentiation. In contrast, H2 receptor activation induces neural stem cell proliferation. 228 H3 receptor is localized in the brain. 229 H3 receptor is an important therapeutic target for cognitive disorders. 230 The neurological function of the H4 receptor remains unclear. 229 H4 receptor can be detected in the non-neuronal cells of the brain. 229 H4 receptor activation is involved in the inflammatory responses regulated by mast cells, eosinophils, and T cells. 229 Histamine acts on H1 and H3 receptors to control normal sleep/wake behavior. 231 Alterations in histamine signaling are found in both neurodegenerative and psychiatric disorders. 230 Due to structural similarity, H1 and H4 receptors are suggested to have cross-functional impacts on disease development. Positron emission tomography results show that reduced H1 or H4 receptor is present in a subgroup of Alzheimer's disease, schizophrenic and depressed patients. [232][233][234] The role of histamine signaling in Alzheimer's disease remains controversial due to the conflicting results on histamine levels. 232 H1 receptor upregulation is associated with myelin damage mediated by focal lymphocytes in multiple sclerosis. 235 Targeting the H3 receptor with selective antagonists could stimulate the release of crucial neurotransmitters, including acetylcholine, dopamine, norepinephrine, and histamine. 236 H4 receptor is involved in M1-activated microglia cells (primary inflammatory cells in the brain) driven neuroinflammation. Attenuating H4 receptor signaling is beneficial in controlling inflammation propagation in Parkinson's disease. 237 Melanin-concentrating hormone receptor. Melanin-concentrating hormone (MCH) is the pro-melanin expressed by the central nervous system. 238 MCH is well documented for its function in controlling motivated behaviours, including feeding and drinking. 239 Later studies suggest that MCH promotes non-REM sleep and modulates energy homeostasis. 240,241 MCH receptor 1 is a stress modulator regulating fear and anxiety processes. 242 MCH receptor 1-signaling is responsive to physiological-or neurochemical-controlling stress and affective states in genetically knockout models. 243 MCH is associated with behavioural disorders and depressive symptoms observed in Huntington's disease patients. 244 Animals without MCH receptor expression exhibit schizophrenia-like phenotypes. 245 Melatonin receptor. Melatonin (MT) or N-acetyl-5-methoxytryptamine is a neuroendocrine hormone produced by the pineal gland. MT is a regulator of the circadian rhythm (sleep-wake cycle). Melatonin is converted from tryptophan/ serotonin in the pinealocytes. Melatonin also functions as an antioxidant to protect tissues from free radical damage. 246 The antioxidant activity of melatonin is essential in tissue (such as the brain) with high reactive oxygen species (ROS) resulting from oxygen consumption. 247 Peripheral tissues, such as the gut and skin, could also secrete melatonin. 248 Melatonin secretion is suppressed by daylight through the retino-hypothalamic tract and reaches a peak at night. Rhythmic nocturnal secretion (secreted in the dark) allows melatonin to distributes throughout the body via circulation.
Circadian rhythm dysregulation is a common symptom presented by patients with neurodegenerative disease due to functional impairment of the retina-suprachiasmatic nucleus (SCN)-pineal axis. 249 In Alzheimer's disease, melatonin and MT1 receptor level in SCN and cortex diminishes remarkably. 250,251 Pathological α-synuclein aggregation (a stepwise aggregation of presynaptic neuronal protein observed during Parkinson's disease development) is reduced in animal models subjected to melatonin treatment. 252,253 In multiple sclerosis and amyotrophic lateral sclerosis, melatonin demonstrates anti-apoptotic functions and offers neural protection from oxidative damage. 254,255 Dysregulation in MT1/2 receptor signaling contributes to the pathological development of anxiety, sleep disorders (insomnia), and depression. [256][257][258] In a post-mortem study on depressed patients, hypothalamic MT1 expression increased in the hypothalamic suprachiasmatic nucleus and is correlated with disease duration. 259 Melatonin treatment can alleviate symptoms of psychiatric disorders with few side effects (even at high dosages). 260 Exogenous melatonin may also be administered to control anxiety. 261 Melatonin is an effective medication for sleep disturbances in depression. 262 However, no solid empirical evidence supports melatonin or melatonin receptor agonists as the cure for depression. The use of melatonin to normalize the disrupted circadian cycle might not be sufficient to alleviate depression.
Sphingosine 1-phosphate (S1P) receptor. S1P is an active lysophospholipid. S1P exerts its biological functions through S1P receptor 1-5. 263 S1P/S1P receptor controls angiogenesis, chemotaxis, and egress of lymphocytes (from bone marrow, thymus, and lymphoid tissues). 263 S1P receptor-expressing immune cells in lymphoid tissues are attracted by the high S1P level in the bloodstream. 264 S1P receptors on immune cells are inactivated in peripheral blood by receptor internalization. 264 S1PR1 can be found in B, T, and dendritic cells. 263 During inflammation, S1PR1 on immune cells is upregulated. 265 S1PR1 enhances inflammation by activating neuroglia/microglia (immune cells orchestrating inflammatory response in the central nervous system). 266 S1PR1 might contribute to the development of multiple sclerosis by promoting chronic and acute inflammation. 263,267 Unlike S1PR1, S1PR5 is mainly detected in natural killer and dendritic cells. 268 S1PR5 expression on natural killer cells is critical for its egress from lymph nodes and bone marrow. 269 Hence, targeting S1P receptors might protect the brain from immune attacks by limiting lymphocytes from passing through the blood-brain barrier in multiple sclerosis. 266 Opioid receptor. The opioid receptor family is composed of delta (δ)-opioid receptor (DOR), kappa (κ)-opioid receptor (KOR), mu (μ)opioid receptor (MOR), and nociceptin receptor. Opioid receptor recognizes a variety of endogenous neuropeptides, including enkephalins, endorphins, and dynorphins. 270 The endogenous opioids are one of the neuromodulators produced by the body to attenuate stressful states. Opioid receptor in the central and peripheral nervous system regulates stress and pain responses. 271 locus coeruleus (LC) in the brain is the stress-integrating site. The opioid receptor can sensitize neurons in LC to corticotropinreleasing factor (CRF), a potent psychological mediator regulating stress-induced behaviors. 272 Chronic or persistent acute stress can alter LC functions. 273 Hyperactive LC is associated with psychiatric disorders. 274 Dysregulation of the opioid receptors affects emotion processing in patients with major depressive disorders. 275 Opioid receptor levels are related to neurocognitive deficits. 276 Elevated opioid receptors level might elicit symptoms of schizophrenia resulting in treatment resistance. 276 δ-opioid receptor and mu-opioid receptor exhibit opposite functions in the pathogenesis of Alzheimer's disease. δ-opioid receptor agonist reduces expression of β-site APP cleaving enzyme 1 (BACE1), which cleaves amyloid precursor protein to initiate Aβ peptide production in PC12 cells (harbouring mimicked injury of Alzheimer's disease). 277,278 On the contrary, knocking down δ-opioid receptor increases BACE1 expression, leading to high production of Aβ42, the essential pathogenic Aβ peptides in Alzheimer's disease with 42 amino acids. 278 For the μ-opioid receptor, it is noted that agonist-induced receptor activation enhances BACE1 and Aβ42 expression. 278 Hence, targeting δ-opioid/μ-opioid receptor signaling might benefit Alzheimer's disease treatment; Parkinson's disease patients have reduced brain kappa-opioid receptor levels. 279 Activating κ-opioid receptor ameliorates Parkinsonian behaviours and restores locomotor in marmoset with Parkinsonism. 280 In addition, κ-opioid receptor agonists can alleviate dyskinesia behaviour derived from L-DOPA in Parkinson's disease rats. 281 Serotonin receptor. Dysregulation of serotonin (5-hydroxytryptamine, 5-HT) receptors is observed in nearly all neurodegenerative and psychiatric disorders. 282,283 5-HT receptors 1 and 2 are the most intensively studied drug targets. The receptors have various effects with multiple subtypes and alternative splice variants. 5-HT1 and 5-HT2 receptors have different expression patterns in the brain with similar or opposite functions. 284 5-HT1 receptor has 5 subtypes: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F receptors. 5-HT1A receptor can be found in both serotonin neurons and non-serotonin neurons. 285 5-HT1A receptor is associated with anxiety and mental traits in transgenic mice. 285 Partial agonists targeting the 5-HT1A receptor are suggested to be useful in controlling alcohol abuse. 286 Anterior cingulate cortex (ACC) is a brain region regulating emotion regulation, pain perception, and cognitive control. 287 Patients with bipolar disorder, major depressive disorder, and schizophrenia have higher 5-HT1B receptor expression in the outer ACC layers compared to the inner ACC layers; 288 5-HT2 receptor has 3 subtypes: 5-HT2A, 5-HT2B, and 5-HT2C receptors. 5-HT2 receptors are implicated in various neuropsychiatric phenotypes, including schizophrenia, attention deficit hyperactivity disorder, affective disorders, eating disorders, anxiety disorders, obsessivecompulsive disorder, suicide, and Alzheimer's disease. 289 Class C (glutamate) Structural insights. Class C GPCRs are distinguished from other classes of GPCRs by two unique features. First, the orthosteric ligand binding pocket is located in the large extracellular venus flytrap domain (VFT). VFT is connected to the transmembrane helix via the cysteine-rich domain (CRD) (Fig. 4c). Among class C GPCRs, only the GABAB receptor lacks CRD; Second, class C GPCR forms hetero-or homo-dimers at physiological conditions. [290][291][292][293][294] VFT domain forms an asymmetric dimer interface to facilitate dimer formation. Ligand engagement at either subunit is sufficient to activate the receptor. 291,294,295 The surface interface between dimers is the potential binding site for the therapeutic modulator. 292 The conformation rearrangement between ICL2 and ICL3, and C-terminus contributes to receptor activation. [296][297][298] γ-aminobutyric acid B receptor. γ-aminobutyric acid B (GABAB) is an inhibitory neurotransmitter. GABAB receptor is a heterodimer consisting of two subunits, GABAB1 and GABAB2. GABAB1                  expression is reduced in the brain of Alzheimer's disease patients. The GABAB1 protein level is negatively associated with the neurofibrillary tangle. 299 Results from a genome-wide association study (GWAS) show that GABAB1 SNPs are a risk factor for schizophrenia. 300 GABAB2 SNPs are correlated with the development of Huntington's disease. 301 Activating GABAB receptor can ameliorate motor impairment and reduces inflammation/ oxidative damage in Parkinson's disease models. 302 Metabotropic glutamate receptors. The excitatory neurotransmitter glutamate mediates neuronal excitability via metabotropic glutamate receptors (mGluRs). Functional mGluR is a homodimeric receptor consisting of 8 members (mGluR1-8). 303 Dysregulation of mGluR signaling pathways is observed in both neurodegenerative and psychiatric disorders. 304 Group I mGluR composes of mGluR1 and mGluR5. mGluR1 localizes in the hippocampus, hypothalamus, periaqueductal gray, and amygdala, which are associated with anxiety. 305 mGluR5 activity is linked to the cognitive symptoms of Alzheimer's disease. [306][307][308] Deleting mGluR5 improved spatial learning impairment and decreased Aβ oligomers in Alzheimer's disease models. 309 Interaction between mGluR5 and cellular prion protein could also play a part in the pathogenesis of Alzheimer's disease. 310,311 Activating mGluR5 promotes striatal neuron survival in Huntington's disease models. 312,313 mGluR5 knockout mice exhibit obvious schizophrenia symptoms, including reduced spatial memory and reduced sensorimotor gating. 314 Group II mGluR consists of mGluR2 and mGluR3. Activating mGluR2 and mGluR3 can control panic-like behaviors and ameliorates acute stress responses in the anxiety model. 315 Mutant huntingtin in Huntington's disease is toxic to neurons. 313 In the mouse model, activating mGluR2 and mGluR3 could enhance limb coordination by attenuating the generation of huntingtin aggregate. 316 mGluR2 and mGluR3 demonstrate protective effects on the nigrostriatal system, which restores functional deficits in Parkinson's disease rat model. 317,318 Overexpression of mGluR2 in the neocortical layers, cerebellum, striatum, hippocampus, and thalamus/hypothalamus could build up glutamate-mediated excitotoxicity and promote Huntington's disease progression. [319][320][321][322] Group III mGluR includes mGluR4/6/7/8. mGluR4 activation ameliorates locomotion disorder in Parkinson's disease rats. 323 mGluR7/8 are associated with the anxiety-related phenotype. 324,325 SNPs in mGluR7/8 are correlated to the susceptibility of schizophrenia. [326][327][328][329] GPCR dimers. GPCRs can function in homodimeric or heterodimeric forms. 330,331 The receptor complex consists of one GPCR dimer with two orthosteric binding sites and a heterotrimeric G protein. 332 GPCR dimer exhibits different biochemical properties compared to the individual receptor. Activation of either one of the receptors is sufficient to promote dimer formation. 333 Dimeric GPCR has a different ligand binding affinity as compared to the monomer. 331 Receptor dimerization affects receptor trafficking in agonist-induced GPCR endocytosis. 330 Closely related GPCR subtypes are more efficient in forming heteromers. 334 Here, we focused on discussing two physiologically existing GPCR heterodimers (A2AR-D2R and mGluR2-5-HT2A).
Adenosine 2A receptor-dopamine D2 receptor (A2AR-D2R) heterodimer is located in the ventral striato-pallidal GABA neurons. 335,336 A2AR-D2R heterodimer attracts attention in the field of Parkinson's disease medication as ligands for A2AR can modulate dopamine signaling in Parkinson's disease. Coadministration of dopamine precursor L-DOPA (L-3,4-dihydroxyphenylalanine) and dopamine receptor agonists could improve mobility in Parkinson's disease. 141 It has been shown that adenosine antagonists such as caffeine could enhance dopamine agonist action in Parkinson's disease treatment. 337 A2AR activation can suppress D2R-mediated Gi/o signaling. 335 Stimulating A2AR with adenosine A2AR agonist in the nucleus accumbens produces behavioural effects similar to local dopamine depletion. 338 Thus, the action of A2AR modulators should be considered in the drug design for Parkinson's disease.
Serotonin type A 5-HT2A receptor and type C metabotropic glutamate 2 (mGlu2) receptor regulates psychoactive behavior in schizophrenia. 339,340 5-HT2A receptor is a Gq-coupled receptor, while mGluR2 receptor signals through Gi. 341   receptor is upregulated in the frontal cortex of schizophrenic subjects compared with normal subjects. In contrast, the expression level of mGluR2 is decreased. 341 Balance between Gq and Gi is a predictive indicator of antipsychotic drug properties. 342 5-HT2A receptor and mGluR2 can form stable complexes in physiological conditions which regulate Gq-Gi balance cooperatively. 343 mGluR2 agonist reduces 5-HT2A receptor/Gq signaling in the frontal cortex of schizophrenic subjects. 341 mGluR2 agonist can downregulate 5-HT2A receptor expression. 344 On the contrary, it has been shown that the 5-HT2A receptor controls mGluR2 expression at the epigenetic level in the frontal cortex. 342 Although the 5-HT2A receptor and mGluR2 regulate the activity of each other remains elusive, interrupting the functional crosstalk in the 5-HT2A receptor/ mGluR2 complex is a putative approach in schizophrenia treatment. 345

THERAPEUTIC DEVELOPMENT
The small molecules regulate GPCR activity by stabilizing receptors at unique conformational state (Fig. 5). To explore the GPCRsbased therapeutic strategies against neuropsychiatric disorders, we examined the clinically approved drugs (Fig. 5a) and compounds being tested in different stages of clinical trials (Fig.  5b) in the DrugBank database (https://go.drugbank.com/). In total, 92 drugs are being approved (Table 2). Forty-one candidates are undergoing clinical trials (Table 3). Selected receptors/drugs interaction are shown in Fig. 6.

Neurodegenerative diseases
Alzheimer's disease. Alzheimer's disease (AD) is a progressive neurodegenerative disease. AD patients present with cognitive deficits, memory loss, and personality and behaviour changes. Currently, there is no curative treatment for AD. Reducing patients' symptoms and delaying the disease's progression is the primary objective of treatment. α1-adrenergic receptor, dopamine receptor, muscarinic acetylcholine receptor M3, histamine H1 receptor, and serotonin receptors are the primary therapeutic targets. Medication to control mental symptoms is another important objective, as patients manifest neuropsychiatric symptoms frequently.
phase III clinical trial (NCT04570085). 350 Guanfacine is an α2a-adrenergic agonist. 351 Guanfacine could increase brain noradrenaline levels. Dual actions of Guanfacine on noradrenergic transmission and thalamocortical glutamatergic transmission have been reported. 352 Guanfacine is a drug for treating children's attention deficit/hyperactivity disorder (ADHD). The efficacy for improving cognition in AD is evaluated in the phase III trial (NCT03116126). The α1-adrenergic receptor antagonist, Prazosin, is being tested for its effectiveness on agitation in adults with AD in a phase III trial (NCT03710642). Prazosin is a drug for hypertension, benign prostatic hyperplasia, and post-traumatic stress disorder (PTSD) associated nightmares. Prazosin can cross the blood-brain barrier and act on the active α1-adrenoreceptor in the brain.
Brexpiprazole is classified as a novel class of antipsychotic with serotonin-dopamine modulating functions. It is an atypical antipsychotic that function as a partial agonist for serotonin and dopamine receptors. As a partial agonist, Brexpiprazole exerts smaller responses than the native ligands. 353,354 The use of Brexpiprazole in AD agitation is now in phase III study (NCT03620981).
Parkinson's disease. Parkinson's disease (PD) is the second most prevalent age-related disorder. Early stage with mild symptoms did not require medication. Dopamine-like agonists, also known as dopamine-replacement therapy, are the primary treatment for symptomatic PD. As degeneration of the substantia nigra leading to striatal dopamine reduction is a leading cause of PD, reintroducing dopamine can improve motor problems dramatically and slow down PD progression. 348,355 Levodopa is a dopamine precursor. It has long been used in controlling bradykinetic symptoms in PD. Levodopa can cross the blood-brain barrier and is known as a well-tolerated drug for dopamine-replacement therapy. 356 However, Levodopa could lead to motor and psychiatric side effects. 357 Amantadine could reduce dyskinesia (involuntary movements) in PD patients receiving Levodopa. 358 Amantadine is an antiviral medicine with Fig. 6 Interactions between neuropsychiatric drugs with key residues in the orthosteric ligand binding pocket of GPCRs (e.g., adrenoceptors, dopamine receptors, histamine receptors, melatonin receptors, S1P1/5 receptors, and serotonin receptor). The small molecules regulate GPCR activity by stabilizing receptors at unique conformational state antiparkinsonian effects. Synergistic effects are observed when used in combination with Levodopa. 359,360 Lisuride functions as a dopamine receptor agonist with 5-HT1A receptor agonist and 5-HT2B receptor antagonist for PD treatment. 361 Piribedil is a dopamine agonist used with or without Levodopa in a phase III trial to treat idiopathic PD (NCT01519856). 362 Bromocriptine is a dopamine D2 receptor agonist for early PD treatment. Bromocriptine works by activating post-synaptic dopamine receptors. 363 Apomorphine is a morphine derivative. It functions as a D2 dopamine agonist for treating hypermobile "off" episodes of advanced PD, a stage in which PD symptoms get worse even with scheduled medication. It also prevents dyskinesia by functioning as a 5-HT1A receptor agonist. 364 The A2A receptor in the basal ganglia is involved in the motor control of PD. 365 At present, Istradefylline is the principal adenosine A2A receptor antagonist employed in adult PD patients presenting "off" episodes associated with Levodopa treatment. 141 Pergolide is a long-acting dopamine receptor agonist approved in 1982 for treating PD. It functions on various GPCRs, including dopamine D2/3 receptor, α1/2-adrenergic receptor, and 5-HT receptors. It is used as adjunct therapy with Levodopa and carbidopa in the symptomatic treatment of PD. 366 Ropinirole is a non-ergoline dopamine agonist, approved as monotherapy and as an adjunct to Levodopa in the treatment of PD. 367 Benztropine is used to treat the molecular mechanism of anticholinergics PD. 368 Benztropine inhibits dopamine uptake and exhibits varied binding affinities for muscarinic acetylcholine M1 and histamine H1 receptors. 369 Biperiden, another anticholinergic drug launched in 1954, has an antagonistic effect on the muscarinic acetylcholine receptor. 368 Pramipexole is a non-ergot-derived dopaminergic agonist for PD treatment. Pramipexole treatment enhances DA and 5-HT neurotransmission and increases tonic activation of post-synaptic D2 and 5-HT1A receptors in the forebrain. 370 Apart from PD, Pramipexole can also be prescribed for psychiatric conditions such as treatment-resistant depression and bipolar disorder. 371 Multiple sclerosis. Multiple sclerosis (MS) results from an immune attack by infiltrating inflammatory leukocytes in the central nervous system, causing hard, mottled pathologic changes and nerve conduction disorders. 372,373 At present, medication aims to control GPCR-regulated immune cell function as one of the treatment regime for MS. In the database, 6 GPCR-related drugs are recorded. The drugs target multiple GPCRs, including adrenergic receptors, cannabinoid receptors, dopamine receptors, GABA receptors, opioid receptors, orphan GPCRs (GPR12/18/55), S1PR1/5, and chemokine receptors.
Baclofen is a derivative of the neurotransmitter γ-aminobutyric acid (GABA). Baclofen can help relax the stiff muscle (muscle spasticity) experienced by MS patients. Cannabidiol (CBD), one of the active components in cannabis, could improve mobility in MS by reducing depression, fatigue, inflammation, pain, and spasticity (stiff muscle with feelings of pain or tightness) in MS patients. 374 Modafinil is a partial agonist for brain α1b-adrenoceptor. Pharmacological blockade of α1b-adrenoceptor shows benefit in controlling fatigue syndromes in MS. Modafinil exhibits clinical efficacy in psychiatric conditions, including treatment-resistant depression and attention deficit/hyperactivity disorder. 375 Ozanimod, Siponimod, and Fingolimod are S1PR agonists that selectively bind to the S1PR1 and S1PR5 subtypes, inhibiting lymphocyte egress from lymph nodes. 376 Ozanimod demonstrates a favourable safety profile in trials. 377 Fingolimod may cause undesirable effects because of its interaction with other S1PR subtypes. Compared to Fingolimod, Siponimod has fewer offtarget effects.
Ceralifimod is a selective S1PΡ1/5 agonist under investigation in phase II clinical trial NCT01226745 in patients with relapsingremitting multiple sclerosis (a condition with relapses or exacerbations of old and new symptoms). 267 Plozalizumab is another potential drug for MS treatment. It is a humanized anti-CCR2 monoclonal antibody targeting white blood cells. 378 Plozalizumab may regulate inflammatory responses by targeting the CCL2-CCR2 axis in MS.
Huntington's disease. Huntington's disease (HD) is a hereditary neurodegenerative disease. Symptoms include movement disorders and cognitive and psychiatric manifestations. Blocking and antagonizing dopamine are effective for HD treatment. Tetrabenazine is a reversible vesicular monoamine transporter 2 (VMAT) inhibitor that inhibits the reuptake of neurotransmitters in presynaptic neurons. VMAT helps to repackage the unbound dopamine taken up by the pre-synaptic terminal. Although it is first designed for schizophrenia treatment, clinical trials demonstrate efficacy in treating hyperkinetic movement disorders. 379 Tetrabenazine also functions as a D2 post-synaptic receptor blocker at high doses and is used to treat uncontrolled muscle movement in HD. 379 Haloperidol is a first-generation antipsychotic for schizophrenia and psychotic disorders. 380 As a dopamine receptor antagonist, Haloperidol is used off-label for managing chorea associated with HD. 381 For cognitive impairment, no effective targeted therapy is available at the present stage. Tiapride is in phase III for the treatment of HD (NCT00632645). Preclinical pharmacologic and behavioral research suggests that Tiapride is a selective blocker of dopamine D2 and D3 receptors in limbic brain regions. 382 Psychiatric disorders Schizophrenia. Schizophrenia is characterized by cognitive deficits and positive and negative symptoms with complex inheritance patterns. 383 Patients may have positive, negative, cognitive, and general psychopathological disorders. According to the positive and negative syndrome scale (a psychiatric rating system), positive symptoms include delusions, hallucinations, conceptual disorganization, hallucinatory, excitement, grandiosity, suspiciousness, and hostility; Negative symptoms include blunted affect, emotional withdrawal, poor rapport, passive social withdrawal, difficulty in abstract thinking or stereotyped thinking and lack of spontaneity and flow of conversation. Schizophrenia patients could also present general cognitive disorders. Examples include anxiety, guilt feeling, tension, depression, poor attention or impulse control, and active social avoidance. 384 Schizophrenia treatment is challenging because existing antipsychotics are antidopaminergic drugs that improve only positive symptoms such as agitation and aggression but have limited efficacy for negative and cognitive symptoms. 385 Globally marketed antipsychotic drugs include typical antipsychotic drugs (mostly specific dopamine D2 receptor antagonists) and atypical antipsychotic drugs (such as dopamine D2 and 5-HT2A dual antagonists and D2/D3 partial agonists).
Aripiprazole, a blockbuster drug for controlling psychiatric symptoms, has high affinities for 5-HT1A, 5-HT2A, D2, and D3 receptors. It is a partial agonist of D2, D3, and 5-HT1A receptors and a 5-HT2A receptor antagonist. 386 Aripiprazole is also a drug for bipolar disorders. 387 Brexpiprazole, developed by Otsuka, is considered as the pharmacological successor to Aripiprazole. Brexpiprazole can also be used as an adjunct for major depressive disorder. [388][389][390] Cariprazine is a D3/D2 partial agonist with moderate affinity for the 5-HT2A receptor. 391 FDA approved it in 2016 for treating adult schizophrenia and bipolar disorder.
Lumateperone is an antipsychotic targeting multiple GPCRs. It is a post-synaptic dopamine D2 receptor antagonist, a presynaptic dopamine D2 receptor partial agonist, and a 5-HT2A receptor antagonist. 392 Lumateperone can be used for positive & negative symptoms and cognitive dysfunction in schizophrenia. 393 It can also be used in bipolar disorder treatment. 393 Chlorpromazine blocks dopamine receptors, α-adrenergic receptors, and 5-HT receptors. It can quickly control the state of agitation and gradually eliminate hallucinations and delusions. Thus, it can apply as medication to control combativeness and aggressive behaviour in children. 394 Risperidone can be used for various mental disorders, including schizophrenia and mood disorders. Risperidone has high affinities for 5-HT receptors and dopamine receptors and mildly inhibits α1adrenergic receptors and histamine receptors. 395 Olanzapine is developed based on clozapine with structural modification. It was approved to be marketed by FDA in 1996. Olanzapine not only inhibits dopamine receptors but also binds to serotonin receptors, and its affinity with serotonin receptors is far greater than its affinity with dopamine receptors.
Haloperidol is a widely used antipsychotic for positive symptoms of schizophrenia, Tourette syndrome, and behavioural disorders/hyperactivity in children. 396 Haloperidol can block dopamine, α-adrenergic, and serotonin receptors. It is highly selective for dopamine receptors.
Spiperone is a potent dopamine D2 receptor antagonist bearing the butyrophenone scaffold. Although it displayed efficacy in treating drug-resistant schizophrenia, it is not yet approved by the FDA. 397 Zotepine is an atypical antipsychotic drug for treating schizophrenia in Japan. It is a potent dopamine D1/D2 receptor and 5-HT2A receptor antagonist. 398 Medication for schizophrenia is an active research area. Schizophrenia drugs generally target multiple GPCRs. For instance, Brilaroxazine, an investigational antipsychotic drug developed by Reviva, could stabilize the dopamine-serotonin system by partially activating D2, D3, D4, 5-HT1A, and 5-HT2A receptors. In addition, it antagonizes 5-HT6 and 5-HT7 receptors. 399 A phase III clinical trial of Brilaroxazine for the safety and efficacy of the treatment of schizophrenia is now under recruitment (NCT05184335).
Eltoprazine is a piperazine derivative that partially activates the 5-HT1A/2B receptor. 401 It is tested in a phase II trial to investigate the treatment of schizophrenia and cognitive impairment (NCT01266174).
LuAF35700 is an antagonist targeting dopamine receptors, serotonin receptors, and α-adrenergic receptors. 399 The efficacy and safety of the LuAF35700 have been examined in phase III randomized, double-blind trial (NCT02717195).
Roluperidone is a novel 5-HT2A and σ2 receptor antagonist developed by Minerva Neurosciences. 402 Phase III studies have shown that Roperidone may treat negative symptoms in schizophrenia patients without causing post-synaptic dopaminergic blockade due to low or no affinity for dopamine and histamine receptors (NCT03397134).
Depression. The underlying mechanism of depression is not clear. According to the record in the DrugBank database, a total of 31 antidepressants target GPCRs. Examples include tricyclic antidepressants, bioamine neurotransmitters (serotonin, norepinephrine, and dopamine) reuptake blockers, and 5-HT2A receptor inhibitors.
Imipramine and Desipramine are examples of tricyclic drugs for major depressive disorders, anxiety, and ADHD. 403 They have high affinities to 5-HT2C and 5-HT2A receptor subtypes. The pharmacological properties of Amitriptyline are similar to Imipramine. Amitriptyline can inhibit 5-HT reuptake with sedative, hypnotic and anticholinergic effects. A combination of Amitriptyline and Imipramine could block serotonin reuptake in the brain's limbic (emotional) regions.
Currently, monoaminergic alterations involving serotonin receptors are a significant cause of depression. 404 Selective or non-selective 5-HT reuptake inhibitors are the first-line treatment for depression. Representative drugs include Fluoxetine, Paroxetine, and Citalopram. [405][406][407][408][409] Fluoxetine, a weak antagonist of 5-HT2C and 5-HT2A receptors, was approved for marketing in 1988 to treat major depressive disorder. Later, Paroxetine was approved in 1992. It is a highly selective reuptake inhibitor of 5-HT in neurons. Citalopram has a similar function in depression treatment. It is also a serotonin reuptake inhibitor. Nefazodone and Trazodone improve mood by antagonizing 5-HT2A/C receptors. They showed affinity to the 5-HT1A receptor. 410,411 Pindolol can accelerate the effects of selective serotonin reuptake by antagonizing 5-HT1A and β-adrenergic receptors. 405,412 Meanwhile, Mirtazapine and Mianserin have antagonistic properties on 5-HT2A/2C receptors. They exhibit inhibitory effects on presynaptic A2-adrenergic receptors. Both drugs improve sleep duration. 408,413,414 Vortioxetine is a multi-mode antidepressant for major depressive disorder treatment in adults. Vortioxetine inhibits serotonin reuptake. It exerts different effects on different members of the 5-HT receptor. On one hand, Vortioxetine is an antagonist for 5-HT1D, 5-HT3, and 5-HT7 receptors. On the other hand, it is a partial agonist for the 5-HT1B receptor. [415][416][417] Bupropion and its primary metabolite hydroxybupropion function by blocking 5-HT3A receptor. 418 Agomelatine is an atypical antidepressant acting as a melatonin receptor (MT1/2) agonist and a 5-HT2C/2B receptor antagonist. 419 Inhibitors of dopamine (DA) transporters are another class of antidepressants. Nortriptyline can bind directly to the DA transporter to inhibit dopamine uptake. It can be used in treatment-resistant depression. [420][421][422] Brexpiprazole is a partial agonist on the 5-HT1A receptor and D2 receptor. Brexpiprazole can also be used in adult patients with schizophrenia.
Anxiety disorders. Anxiety disorders are the most common psychiatric disorders. Anxiety is accompanied by other psychiatric disorders, including major depressive disorders, substance use disorders, and personality disorders. 424 Partial agonists of the 5-HT1A receptor and selective 5-HT reuptake inhibitors are frequently used in anxiety treatment. 425,426 Buspirone, the partial agonist for the 5-HT1A receptor, is approved for treating anxiety due to neurosis. 427 Paroxetine 428 and Escitalopram, the 5-HT reuptake inhibitors, can relieve anxiety symptoms and prevent recurrence in patients. 409 Trazodone is used to treat anxiety disorders with depressive symptoms and is suitable for patients with significant psychomotor agitation, anxiety, and insomnia. 429 Hydroxyzine is the most studied antihistamine for anxiety and the only FDA-approved antihistamine for treating anxiety. It is commonly used for anxiety, panic attacks, and insomnia in inpatients and outpatients. 429,430 Drug targeting β-adrenoreceptor in the central nervous system can also relieve anxiety. 431 Propranolol, the selective β1/2adrenoceptor antagonist (β-blockers), is the first-line pharmacological treatment for anxiety disorders. 432,433 Doxepin can be used for depression and anxiety. It is an antagonist of the histamine H1 and H2 receptors, 5-HT2A/2C receptors, and the muscarinic acetylcholine receptors (M1-M5). 434 Naluzotan, the selective 5-HT1A receptor agonist, has been investigated for anxiety disorders and depression treatment (NCT00248183). 435 Ansofaxine, a reuptake inhibitor of serotonin, norepinephrine, and dopamine, is a new-generation drug for anxiety management. The drug has completed phase III clinical trials in China to treat anxiety and depression (NCT04853407).
Bipolar disorder. Bipolar disorder (BD) is characterized by periodic mood disorders. Medication is the primary treatment to improve the psychosocial function and quality of life of patients with BD. Pharmacological management of acute depressive/manic episodes and prevention of recurrence is also essential. Atypical antipsychotics for bipolar disorder exhibit high affinities for multiple serotonergic receptors, including 5-HT1A, 5-HT2A-C, 5-HT6, and 5-HT7 receptors.
Quetiapine was approved by the FDA in 1997 for the symptomatic treatment of schizophrenia and is used as a firstline treatment to control depressive episodes of BD. It exerts therapeutic effects may by antagonizing 5-HT1A, 5-HT2A, D1, D2, and H1 receptors as well as α1/2adrenergic receptors. 436,437 Dexmedetomidine is an α2-adrenergic receptor agonist that can be used for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorders. 438 Risperidone, an atypical antipsychotic drug, is now used as maintenance therapy for patients with bipolar I disorder. 439 Tianeptine is a novel antidepressant that stimulates serotonin, increases levels of 5-hydroxyindoleacetic acid in brain tissue and plasma, and decreases serotonin-induced behavior. 440,441 Clinical trials are underway for the adjuvant treatment for BD with Tientidine (NCT00879372). Lumateperone, an antagonist with high binding affinity to the 5-HT2A receptor and moderate affinity to the post-synaptic D2 receptor, is being evaluated for treating BD, depression, and other neuropsychiatric and neurological disorders (NCT03249376, NCT02600507).
Tourette's syndrome. Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by repetitive behaviours, including motor/phonic tics. TS is commonly coupled with obsessivecompulsive disorder (OCD) and ADHD. 442 The underlying mechanism of TS remains poorly clarified. [443][444][445] Abnormalities in synaptic neurotransmission involved in the cortico-striatal-thalamocortical circuitry are implicated in TS pathogenesis. 446,447 Dopaminergic signaling in cortico-striatal-thalamocortical pathways might be associated with TS progression. 444,448,449 α-adrenergic agonists are the first choice in TS treatment. 450 Examples include Clonidine and Guanfacine. 438,451 Aripiprazole is a partial agonist of dopamine D2 and 5-HT1A receptors. It can stabilize dopamine receptor and improves TS symptoms. 452 In contrast, Pimozide exerts a therapeutic effect by inhibiting the dopamine D2 receptor in the central nervous system. 453 Attention deficit hyperactivity disorder. Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder affecting school-age children. It is a neurodevelopmental disorder with multifactorial etiological risk factors. ADHD is characterized by hyperactivity, impulsivity, and ageinappropriate symptoms of inattention. 454 Irregularities in catecholamines circuits in the prefrontal cortex, such as dopamine and norepinephrine, are a leading cause of ADHD. 455,456 Most ADHD drugs are designed to enhance catecholamine transmission in the prefrontal cortex. 457 Methylphenidate can significantly reduce hyperactive behavior, increase attention concentration ability, and effectively improve the core symptoms of ADHD, so it is one of the most widely used first-line drugs approved by the FDA. Methylphenidate blocks dopamine D1 and D2 transporters, resulting in increased levels of synaptic dopamine, and also shows activity against serotonergic 5-HT1A receptors. 351,458,459 Second-line drugs for ADHD include Atomoxetine, Guanfacine, and Clonidine. 351,438,460 Atoroxetine is a non-stimulant medication that acts as a selective norepinephrine reuptake inhibitor in ADHD. 440,461 Guanfacine is a phenylacetyl guanidine derivative, which is more selective than Clonidine in activating the α2adrenergic receptor. 351 Venlafaxine is a new type of selective serotonin and dopamine reuptake inhibitor. It is a dual-channel antidepressant. Venlafaxine inhibits the reuptake of serotonin by neuron endings at low doses and inhibits the reuptake function of neuron endings at a high dose to enhance attention. Amfetamine (AMF) acts on the cerebral cortex and reticular activation system. AMF stimulates adrenalin receptors and enhances neurotransmitter secretion, such as 5-HT and dopamine. 462 Fluoxetine is a potent and selective serotonin reuptake inhibitor for ADHD treatment. 463,464 Edivoxetine is an adrenergic absorption inhibitor. It is now in phase III development for ADHD with hyperactivity (NCT00922636, NCT00965419). Centanafadine is a triplereuptake inhibitor for dopamine, norepinephrine, and serotonin reuptake. It is currently in phase III clinical trials (NCT03605849, NCT03605680, NCT03605836). SGS-742 has been investigated for ADHD treatment. It acts as a GABA-B receptor antagonist and could enhance the release of glutamate, aspartate, glycine, and somatostatin.

EXAMPLE OF EMERGING GPCR TARGETS
Most of the GPCRs targeted by approved drugs for neuropsychiatric diseases belong to class A and C GPCRs. With the advance of biotechnology and increase in understanding of GPCR functions, new candidates are discovered in other GPCR families, including class A (orphan), class B1 (secretin), class B2 (adhesion), class C (calcium-sensing receptor), and class F. Class A (orphan GPCR) Orphan GPCRs are receptors whose cognate ligands are not discovered or validated in cellular/ animal models. Deorphanization with reverse pharmacology is currently an active area in GPCR research.
GPR17. GPR17 is activated by two different endogenous ligands: uracil nucleotides and cysteinyl-leukotrienes. 465 Uracil nucleotides trigger astrocytic migration by upregulating membrane integrins. 466 Cysteinyl-leukotrienes are lipid mediators secreted by inflammatory cells and nervous tissues. 467 Cysteinyl-leukotrienes can stimulate astrocyte proliferation via autocrine signaling. 468 GPR17 is a sensor of local damage to the myelin sheath. GPR17 downregulation promotes the development of mature oligodendrocytes from myelin-producing oligodendrocyte precursors. 469 GPR17 is involved in reconstructing and repairing demyelinating plaques formed by ongoing inflammatory processes. 470 In a mouse model of multiple sclerosis, targeting GPR17 can delay the onset of autoimmune encephalomyelitis. 471 GPR26. GPR26 is a brain-specific GPCR. GPR26 has high sequence homology with purinergic P2Y receptor and serotonin 5-HT5A receptor. 472,473 GPR26 regulates emotion in animal models. GPR26 knockout mice exhibits anxiety-and depressive-like behaviors. 474 Colocalization of GPR26 and neuronal nuclear inclusions is observed in brain tissues suggesting a potential link between GPR26 and neurodegenerative diseases. 473 GPR37 and GPR37L1. GPR37 can be found in pre-myelinating/ myelinating oligodendrocytes, dopaminergic neurons, and hippocampal neurons. 475 GPR37 shares high sequence homology with peptide-activated GPCRs such as endothelin receptor B (ETB). 475 In Parkinson's disease, GPR37 acts as an adenosine A2A receptor inhibitor via receptor oligomerization; 476 GPR37L1, in contrast, is found mainly in astrocytes and oligodendrocyte progenitor cells. 475 GPR37L1 is involved in the adaptive myelination of oligodendrocytes which is critical for neural plasticity, learning, and memory in adults. 477 GPR39. Zinc regulates behavior, cognition, and ability to learn. 478 Dysregulation in zinc homeostasis is associated with progressive dementia and cognitive impairment. Zinc deficiency gives rise to various neuropsychiatric disorders, including epilepsy, seizures, and depression. 479,480 Extracellular zinc can activate zinc-sensing receptor GPR39. 481,482 Zinc stimulates GPR39-mediated signal transduction and induces calcium mobilization in HEK293 cells. 483 Zinc-activated GPR39 increases expression of K + /Cl − cotransporter 2 (KCC2), the Cloutward transporter in neurons. 484 Further, GPR39 increases Na + /H + exchanger activity in hippocampal neurons in a pH-dependent process. 485 GPR40. GPR40 (also known as free fatty acid receptor 1) is the receptor for medium and long-chain unsaturated fatty acids. GPR40 activates the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome pathway by blocking the formation of apoptosis-associated speck-like protein containing a CARD (an inflammasome component). 486 GPR40 promotes hypothalamic neurogenesis by enhancing cell proliferation and survival. 487 GPR40 may associate with the development of epilepsy by altering N-methyl-d-aspartate receptor-mediated synaptic transmission. 488 In Alzheimer's disease model, activating the GPR40 receptor can reduce β-amyloid production and rescue cognitive deficits. 489,490 GPR50. GPR50 exhibits high sequence homology with melatonin MT1/2 receptors. However, melatonin (the endogenous ligand for MT1/2 receptors) cannot bind to GPR50 directly. 491 GPR50 can be detected in the pituitary, hypothalamus, and hippocampus intermedia. 491,492 GPR50 enhances neuronal differentiation via notch and WNT/β-catenin. 493 GPR50 might be involved in psychiatric illness by interacting with neurite outgrowth inhibitor NOGO-A. 494 GPR50 is an X-linked gene (Xq28). It is suggested to be a sex-specific risk factor in bipolar affective disorder, major depressive disorder, and schizophrenia. 495 GPR50 can antagonize the MT1 receptor by forming a heterodimer. 496 The inhibitory effects are mediated via the large C-terminal tail, which blocks the β-arrestin recruitment and G protein coupling. 495 MT2 receptor could also form a heterodimer with GPR50, but the functional consequence remains to be defined. 496 GPR52. GPR52, a striatal-enriched orphan GPCR. GPR52 stabilizes HTT by cAMP-dependent but PKAindependent mechanisms. 497 GPR52 antagonist can ameliorate Huntington disease-like phenotypes by diminishing mHTT protein levels. 498 GPR52 is a potential target of antipsychotic drugs. 499 GPR52 is associated with cognitive function, emotion, and psychosis-related/antipsychotic-like behaviors. 204,499,500 GPR52 has high sequence homology with histamine H2 receptor and 5-HT4 receptor. 204 GPR52 agonist treatment suppresses methamphetamine-induced hyperactivity suggesting that GPR52 might be involved in neurochemical sensitization. 501 Recent study reveals that GPR52 is a self-activating receptor. 502 The extracellular loop 2 is immersed deeply into the typical ligand binding pocket of GPR52, which maintains the constitutive active state at physiological conditions. 503 Super-conserved receptors expressed in the brain. GPR27, GPR85, and GPR173 are super-conserved receptors expressed in the brain (SREB). GRR27 deletion is associated with speech delay, contractures, hypertonia, and blepharophimosis. 504 GPR85 may function as a negative regulator in hippocampal adult neurogenesis and alters cognitive functions, including learning and memory. 505 It has been reported that GPR85 is a risk factor for schizophrenia. 505 GPR173 may function by interacting with phoenixin (a recently discovered peptide controlling reproductive hormone secretion, visceral pain, and pruritus) in hypothalamic neurons, which regulates memory and anxiety. 506,507 In neuronal M17 cells, phoenixin promotes neuronal mitochondrial activity and biogenesis by activating the CREB pathway. 508 Further, binding of gonadotropin-releasing hormone 1-5 (GnRH 1-5) to GPR173 could inhibit neuronal migration. 509 GPR88. GPR88 expresses exclusively in the neuron of the rat brain throughout the striatum. 510 In GABAergic medium spiny neurons (MSNs), GPR88 contributes to tonic GABAergic inhibition and responses to GABA release. 511 GPR88 might play a part in prepulse inhibition of startle, apomorphine-induced climbing, and amphetamine-stimulated locomotor activity. 512 Co-expression of GPR88 and D1 dopamine receptors is found in the brain. 513 In Parkinson's disease (unilateral 6-hydroxydopamine-lesioned rats), GPR88 expression is associated with L-DOPA-mediated behavioural changes. 510 Antidepressant treatments can modulate GPR88 expression in rat brains. 514 Morphine can regulate GPR88 expression in the amygdala via the mu-opioid receptor. 515 GPR88 is genetically associated with various neuropsychiatric disorders, including schizophrenia, bipolar disorder, speech delay, and chorea. 516,517 Class B1 (secretin) Structural highlights. Class B1 GPCRs have a conserved extracellular N-terminal domain (ECD) with a three-layered α-β-β/α fold structure (100 to 160 residues) responsible for the binding of peptide hormones (Fig. 7). [518][519][520] Peptide ligands stabilize receptors by interacting with both ECD and transmembrane core. 521 N-terminus of the peptide interacts with the orthosteric pocket within the transmembrane domain. 522,523 Class B1 GPCRs recognize peptide ligands with different C-terminus, ranging from disordered secondary structures to continuous α-helix. 524,525 Like class A GPCRs, the cavity formed by the receptor cytoplasmic part allows anchoring of the α5 helix of G proteins. 526,527 Among class B1 GPCRs, calcitonin and calcitonin gene-related peptide receptors, corticotropin-releasing factor receptors, and the glucagon receptor family are frequently reported to be involved in neurodegenerative diseases and psychiatric disorders.
Receptors for calcitonin and calcitonin gene-related peptides. Calcitonin (CT) and calcitonin gene-related peptides (CGRPs) are ligands of the CT receptor. CGRPs also exert their biological functions through CL (calcitonin receptor-like) receptors. 528 The activity of CT and CL receptors is modulated by receptor activity-modifying protein (RAMP 1-3 ). 529 CT receptor-RAMP complexes can also interact with amylin. Therefore they are also known as amylin receptors (AMY 1-3 ). 529 CT receptors are implicated in neuroinflammation in Alzheimer's disease. 530 Antagonists targeting amylin receptors might be beneficial for Alzheimer's disease treatment. 531 Corticotropin-releasing factor receptor. Corticotropin-releasing hormone (CRF) regulates the neuroendocrine stress response. 532 CRH exerts its biological function through two receptors: CRFR1 and CRFR2. Human corticotropin-releasing factor receptor 1 (CRFR1) exhibits widespread distribution in the central nervous system. In contrast, human CRFR2 is predominately expressed in peripheral tissues. 532 CRFR1 signaling shows sex divergence in Alzheimer's disease. 533 CRFR1 antagonist treatment delays Alzheimer's disease symptoms, including cognitive impairment and accumulation of Aβ amyloid plaques, by regulating oxidative stress in transgenic mice. 534 CRF/CRFR1 signaling plays a crucial role in stress-induced behaviour. 532 It has been shown that noise exposure can increase CRF/CRFR1 expression in the hippocampus. 535 CRFR1 could sensitize 5-HT2 receptor signaling to modulate anxiety behavior. 536 In addition, CRFR1 antagonist modulates gamma-aminobutyric acid (GABA)-ergic activity in the brain and controls fear response in rat anxiety models. 537 Singlenucleotide polymorphisms of CRFR1/2 are positively associated with major depressive disorder. [538][539][540] Glucagon receptor family. The glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1/2 (GLP-1/2) are gut peptide hormones. 541 The hormones can pass through the bloodbrain barrier. 542 GIP and GIP receptors are expressed throughout the central nervous system. 543,544 Protease-resistant analog of GIP is designed to treat type 2 diabetes mellitus by controlling weight and improving glycaemic control. 545,546 Clinical trials indicate that GIP and GLP-1 analogs exhibit therapeutic effects for neurodegenerative diseases. 547 GLP-1 enhances the supportive function of astrocytes to neurons. 548 Activated GLP-2 receptor protects hippocampal cells from glutamate-induced cell death and increases the growth of astrocytes. 549 GLP-1 mimetic reduces oxidative stress and inflammation and promotes neuron formation. 550,551 GIP can alleviate amyloid beta-induced toxicity in Alzheimer's disease and relieve symptoms of Parkinson's disease. 541,542 Class B2 (adhesion) Structural highlights. Class B2 GPCR, also known as adhesion GPCR, has a large extracellular domain (ECD). ECD is responsible for the adhesive function exhibiting high structural diversity (Fig. 8a, b). 552 Adhesion GPCRs are essential for the early development of the nervous system and the brain. 553 The receptor allows neural cells to communicate with the surrounding environment and migrate to destinate sites to carry out specific functions. 554 In mouse Purkinje neurons, adhesion GPCR is required to generate intricate dendritic structures for synaptic connections. 554 Adhesion GPCRs are further classified into ADGRL, ADGRE, ADGRA, ADGRC, ADGRD, ADGRF, ADGRB, ADGRG, and ADGRV subfamilies. 555 Nearly all class B2 orthologs have the GPCR autoproteolysis inducing domain (GAIN). The GAIN domain is located at the juxtamembrane region. 556 GAIN domain is crucial for the maturation and function of adhesion GPCR. GAIN possesses intrinsic autoproteolytic activity and cleaves at the integral cysteine-rich GPCR proteolysis site (GPS). 556 Autoproteolysis give rise to two noncovalently associated fragments: N-terminal fragment (NTF) with most of the extracellular domain; and C-terminal fragment (CTF) consisting of a small proportion of the GAIN domain and most of the entire transmembrane domain (Fig. 8a). 554,557,558 The activation mechanism of adhesion GPCR is the least understood among different GPCR classes. Most adhesion GPCRs are orphan GPCRs as their natural ligands remain poorly defined. 552 Receptor activation may follow the tetheredpeptide-agonist models. 558 The stalk region bends approximately 180º downward into the core of the 7TM domain, which functions as tethered agonist to initiate G protein signaling (Fig.  8c). 559,560 Cleavage-independent mechanisms may exist for receptor activation. 560 Ligand binding at the GAIN domain might induce conformational changes, which initiate transient G protein signaling. 561 Upon activation, the intracellular milieu is in the open conformation facilitating G protein coupling. Adhesion GPCRs could employ non-G protein such as PDZ/SH3 domain-proteins and arrestins for signal transduction. 562 Examples of class B2 GPCR. Adhesion G protein-coupled receptor B1 (ADGRB1 or brain-specific angiogenesis inhibitor 1, BAI1) regulates synaptic plasticity in learning and memory processes in the hippocampus. 563 ADGRB1 is a post-synaptic receptor controlling excitatory synapse development. 564,565 Forced ADGRB1 attenuates toxin-induced neuronal cell death. 566 ADGRB1 is associated with dopaminergic neuronal loss in Parkinson's disease. 566 Adhesion G protein-coupled receptor B3 (ADGRB3) is enriched in post-synaptic density and cerebellar Purkinje cells. 563,567,568 ADGRB3 modulates synaptic connection in the cerebellum. 568 SNPs and gene amplification in ADGRB3 are associated with familial schizophrenia. 569 Other psychiatric conditions, such as bipolar disorder, are suggested to be linked with ADGRB3. 570 Adhesion G protein-coupled receptor L3 (ADGRL3) is genetically associated with attention deficit/hyperactivity disorder (ADHD) in adults. 571 Knockout mice models show enhanced locomotive activity, improved levels of impulsivity, and working memory deficits. 572 Maternal smoking during pregnancy is an environmental risk factor for ADHD. 573 In fibroblast cells, nicotine exposure could stimulate ADGRL3 expression. 571 The downstream ADGRL3 signaling events leading to ADHD remains poorly defined. 574 ADGRL3 might alter monoaminergic signaling by modulating the expression of dopamine and serotonin transporters. 575 Class C (glutamate) Calcium-sensing receptor. Calcium-sensing (CaS) receptor participates in the regulation of Ca 2+ homeostasis. In Alzheimer's disease model, elevated expression of CaS receptor is observed in the hippocampal CA1 area and dentate gyrus, which is in accord with the β-amyloid plaques increase. 576 CaS receptor impeding amyloid-β42 oligomers (Aβ42-os) proteolysis via direct interaction, leading to Aβ42-os aggregation and oversecretion. 577 CaS receptor inhibitor sustains mental competence by promoting Aβ42 proteolysis. 577 Inhibiting the CaS receptor improves memory and cognitive defects caused by β-amyloid in mice. 578 CaS receptor might induce cognitive defects via eliciting cytosolic phospholipase A2 and prostaglandin E2 signaling pathway. 578 Class F Structural highlights of Class F GPCR. Class F GPCR contains a large extracellular and cysteine-rich (CRD) domain (Fig. 9). 579 CRD is essential for the stability and activity of class F GPCRs. 580 FZD gene family is highly conserved in mammals with conserved structural features. FZD is a receptor for the WNT family of lipoglycoprotein, which mediates signal transduction via canonical WNT-β-catenin pathway and β-catenin-independent noncanonical pathways. The secretory WNT binds to the cysteine-rich domain at the extracellular side. The Lys-Thr-X-X-X-Trp (KTXXXW) motif located at the C-terminal is essential for activating the canonical WNT/ β-catenin pathway. 581,582 WNT signaling regulates neuronal polarization and axon specification polarity by activating atypical protein kinase C in rat hippocampal neurons. 583 Further, WNT signaling governs collateral or terminal branching of the axon, dendrite outgrowth and guidance, dendritic spine formation, synapse formation/plasticity, and elimination. 584 WNT/FZD signaling alterations are observed in several neurological disorders, including Alzheimer's disease and Huntington's disease. 585,586 The transmembrane region is compact and hydrophilic. 580,587 Similar to class A GPCR, outward bending of TM6 and an inward shift of TM5 at the cytoplasmic side is observed in the active class F GPCR. 580 Class F receptors frizzled (FZD1-10) and smoothened (SMO) are closely associated with embryonic development and tissue homeostasis. 588 Reported FZD ligands include frizzled-related proteins (SFRPs) and R-spondin. 589,590 FZD1 is found in dopamine-synthesizing neurons, which form an astrocyte-DA autoprotective loop via WNT1/FZD1/β-catenin signaling. 591 FZD1 enhances myelin preservation and neuronal survival; 592 FZD3 is genetically related to substance-induced psychosis and schizophrenia; 593,594 Neuronal degeneration observed in amyotrophic lateral sclerosis is regulated by WNT5a/FZD4 signaling. 595 WNT5a/ FZD5 activity is associated with neuronal inflammatory signaling; 596 Genetic FZD6 variants are associated with neural tube defects in the central nervous system; 597 FZD9 deletion is noted in patients with Williams-Beuren syndrome, a rare genetic disorder with mild to moderate intellectual disability or learning difficulties 598 FZD10 may play a role in brain vascular development; 599 SMO is the receptor for hedgehog proteins involved in neuronal/ glial proliferation and tissue regeneration. 600

CONCLUDING REMARKS
GPCRs are cooperatively involved in the manifestations of neuropsychiatric disorders. Elucidating the intrinsic signaling preference of G proteins or arrestins helps to improve drug efficacy and side-effect profiles. GPCR can work in the dimeric form in disease development. Characterizing the allosteric interactions and the functional consequences of GPCR dimers might provide insights into the pathogenesis of neuropsychiatric disorders. Apart from acting directly in the nervous system, GPCRs might contribute to disease development via the immune system. 220 Target identification is challenging as the clinical presentations are resulted from heterogeneous biological, genetic, and environmental factors. Nevertheless, the increasing understanding of GPCR functions opens a new possibility in drug discovery. Most of the drugs targeting GPCR lack subtype-selectivity. 601 Local drug administration may require to avoid debilitating side effects. 602 The development of psychiatric medications remains slow as the pharmaceutical industry pays more attention to antidepressants and antipsychotic drug development. 603 Therefore, developing specific therapeutic modulators which could recognize subtypes with high specificity is crucial for effective drug development. 602 Benefiting from the advances in crystallography and cryoelectron microscopy technology, the resolved GPCR structures increase our understanding of GPCR functions in pathological conditions. Detailed protein structures could reveal crucial ligand binding features in physiological conditions. 215,547,604 Detailed receptor/ligand profile could facilitate lead compound identification and drug optimization. Hence, harnessing our knowledge of molecular mechanisms and structural information of GPCR will be advantageous for developing effective treatments against neuropsychiatric disorders.